CN1108657A - Calanthamine derivatives, a process for their preparation and their use as medicaments - Google Patents
Calanthamine derivatives, a process for their preparation and their use as medicaments Download PDFInfo
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- CN1108657A CN1108657A CN94117062A CN94117062A CN1108657A CN 1108657 A CN1108657 A CN 1108657A CN 94117062 A CN94117062 A CN 94117062A CN 94117062 A CN94117062 A CN 94117062A CN 1108657 A CN1108657 A CN 1108657A
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- carbonyl
- lycoremine
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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Abstract
This application involves the compounds of following formula:
Wherein R1, R2 and R3 are defined as in the description, these compounds are used to treat the memory dysfunction characterized by choline function reduces; The method for being related to the pharmaceutical composition containing these compounds and manufacturing and using these compounds.
Description
The application relates to the compound of following formula:
Wherein:
R
1Be hydrogen, (C
1～C
12) alkyl-carbonyl, (C
1～C
12) alkoxy carbonyl, aryl (C
1～C
12) alkyl amino-carbonyl, single (C
1～C
18) alkyl amino-carbonyl or two (C
1～C
8) alkyl amino-carbonyl;
R
2Be (C
1～C
12) alkyl carbonyl oxy, aryl (C
1～C
4) alkyl carbonyl oxy, (C
1～C
12) alkoxyl group carbonyl oxygen base, aryl-carbonyl oxygen, hydroxyl, (C
1～C
6) carbalkoxy (C
1～C
6) alkoxyl group or hydroxyl (C
1～C
10) alkoxyl group; And
R
3Be hydrogen, halogen or (C
1～C
4) alkyl; Or its a kind of pharmaceutically acceptable addition salt;
Condition is R
2During for hydroxyl, R
1And R
3Can not all be hydrogen.
These compounds are used to alleviate and variously are reduced to the memory machine dysfunction of feature with choline function, as presenile dementia (Alzheimer's disease).
The present invention also provide a kind of can be used for alleviating variously be reduced to the pharmaceutical composition of the memory machine dysfunction of feature with choline function, said composition comprises that consumption is enough to influence cholinergic a kind of compound of the present invention and a kind of pharmaceutically acceptable carrier.
Unless otherwise stated or the expression, all be common to this specification and the appended claims to give a definition.
Term " alkyl " should refer to straight chain or the branched-alkyl that carbon atom number is certain.Example includes but is not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, and straight chain and side chain amyl group, base, heptyl, octyl group, nonyl, decyl, undecyl, dodecyl and pentadecyl.
Term " halo " should refer to chloro, fluoro, bromo and iodo.
Term " aryl " should refer to have 0,1,2 or 3 and be independently selected from (C
1～C
6) alkyl, (C
1～C
6) alkoxyl group, (C
1～C
6) the substituent phenyl of alkyl-carbonyl, halogen or trifluoromethyl.
One embodiment of the invention are the compounds shown in the formula II:
Wherein:
R
1Be hydrogen, (C
1～C
12) alkyl-carbonyl, (C
1～C
12) alkoxy carbonyl, aryl (C
1～C
12) alkyl amino-carbonyl, single (C
1～C
18) alkyl amino-carbonyl or two (C
1～C
8) alkyl amino-carbonyl;
R
2Be (C
1～C
12) alkyl carbonyl oxy, aryl (C
1～C
4) alkyl carbonyl oxy, (C
1～C
12) alkoxyl group carbonyl oxygen base, aryl-carbonyl oxygen, hydroxyl, (C
1～C
6) alkoxy carbonyl (C
1～C
6) alkoxyl group or hydroxyl (C
1～C
10) alkoxyl group;
R
3Be hydrogen or halogen; And pharmaceutically acceptable addition salt;
R on the condition
2During for hydroxyl, R
1And R
3Can not all be hydrogen.
In the formula II compound of a preferred embodiment, R
1Be hydrogen, (C
1～C
12) alkyl-carbonyl or (C
1～C
12) carbalkoxy; R
2Be (C
1～C
12) alkyl carbonyl oxy, phenyl carbonyl oxygen base, (C
1～C
12) alkoxyl group carbonyl oxygen base, (C
1～C
6) alkoxy carbonyl (C
1～C
6) alkoxyl group or hydroxyl (C
1～C
6) alkoxyl group; And R
3It is hydrogen or halogen.
More preferably, R
1Be hydrogen, (C
1～C
8) alkyl-carbonyl or (C
1～C
6) alkoxy carbonyl; R
2Be (C
1～C
10) alkyl carbonyl oxy or phenyl carbonyl oxygen base; And R
3Be hydrogen or bromine.
Most preferably, R
1Be hydrogen, methyl carbonyl, ethyl carbonyl, sec.-propyl carbonyl, tertiary butyl carbonyl or n-heptyl carbonyl; R
2Be methyl carbonyl oxygen base, ethyl oxy carbonyl, sec.-propyl carbonyl oxygen base, tertiary butyl carbonyl oxygen base, n-heptyl carbonyl oxygen base or phenyl carbonyl oxygen base; And R
3Be hydrogen or bromine.
Another type compound of the present embodiment is R
1Be hydrogen, (C
1～C
12) alkyl-carbonyl or (C
1～C
12) carbalkoxy, R
2Be (C
1～C
12) alkoxyl group carbonyl oxygen base, and R
3Compound for the formula II of hydrogen or bromine.
More preferably R
1Be hydrogen, (C
1～C
10) alkyl-carbonyl or (C
1～C
6) carbalkoxy; R
2Be (C
1～C
6) alkoxyl group carbonyl oxygen base; And R
3Be hydrogen or bromine.
R most preferably
1Be hydrogen, methyl carbonyl or tert-butoxycarbonyl; R
2Be methoxyl group carbonyl oxygen base, oxyethyl group carbonyl oxygen base or tert.-butoxy carbonyl oxygen base; And R
3Be hydrogen.
The another type compound of the present embodiment is R
1Be hydrogen, (C
1～C
12) alkyl-carbonyl or (C
1～C
12) alkoxy carbonyl, R
2Be (C
1～C
6) alkoxy carbonyl (C
1～C
6) alkoxyl group or hydroxyl (C
1～C
10) alkoxyl group, and R
3Compound for the formula II of hydrogen or bromine.
Compound of the present invention is by following abundant description and be shown in the suitable optically active isomer preparation of the lycoremine of reaction mechanism 1.
Reaction mechanism 1
Intermediate 6-demethylation lycoremine shown in the formula IV is a kind of known compound, by a kind of novel method, promptly uses the highly basic salt of sulfur alcohol, for example uses E
tSLi, E
tSNa or E
tSK handles the lycoremine of formula III and prepares.This reaction is generally carried out in polar aprotic solvent such as dimethyl formamide (DMF) or N-Methyl pyrrolidone or protonic solvent such as butanols or amylalcohol, and temperature of reaction is about 80 ℃ to about 135 ℃, preferred about 90 ℃ to about 125 ℃.
R
4For the formula V compound of alkyl or aralkyl prepares as follows: at alkali such as 4-Dimethylamino pyridine, triethylamine or 1, there be compound and the suitable anhydride reactant of monovalent that makes formula IV or IV a down in 8-diazabicyclo [5,4,0] 11 carbon-7-alkene.This reaction at about 0 ℃ to about 50 ℃, is preferably carried out under about 15 ℃ to about 30 ℃ generally in aprotic organic solvent such as chloroform or methylene dichloride.
R
4For the formula V compound through type IV of alkoxyl group or the compound of IV a and suitable carbonochloridic acid ester or carbonate reaction prepare.This reaction generally in inert organic solvents such as methylene dichloride in about 0 ℃ to about 50 ℃, preferably carry out under about 15 ℃ to about 30 ℃.
R
5During for alkyl or aryl, the compound of formula V generally in the presence of alkali such as 4-Dimethylamino pyridine (DMAP) with a suitable carboxylic acid anhydride or at alkali as 1,8-diazabicyclo [5,4,0] 11 carbon-7-alkene (DBU) exist down and carboxyl acyl chloride reacts.These reactions at about 0 ℃ to about 50 ℃, are preferably carried out under about 15 ℃ to about 30 ℃ generally in aprotic solvent such as chloroform.
Work as R
5During for alkoxyl group, the compound of formula V and suitable carbonochloridic acid ester react in the presence of amine such as triethylamine; Or in the presence of amine such as DMAP, react with suitable carbonic ether.These reactions in-10 ℃ to about 50 ℃ approximately, are preferably carried out under about 0 ℃ to about 30 ℃ generally in inert organic solvents such as methylene dichloride.
The compound of formula VI can be by the compound of formula V.Work as R
6During for alkylamino or arylamino, the solution that suitable isocyanic ester and compound V form in aprotic solvent such as tetrahydrofuran (THF) is inserted in the sealed tube, reacted about 24 hours to about 120 hours down at about 55 ℃ extremely about 85 ℃, preferably reacted about 60 hours to about 80 hours down at about 60 ℃ to about 70 ℃.On the other hand, work as R
4And R
5When identical, make the compound VI by the compound of formula IV by the suitable isocyanic ester that in sealed tube, use to surpass two moles as mentioned above.
When X is B
rThe time, the compound of formula IV obtains bromated compound with the bromine processing in the presence of amine such as TERTIARY BUTYL AMINE.At first under about-20 ℃ to about-30 ℃ bromine is added in the TERTIARY BUTYL AMINE, then mixture is cooled to-70 ℃ extremely about-78 ℃ approximately, add the lycoremine compound then, in 6 to 10 hours, preferred about 8 hours, heated mixt was to room temperature.This reaction generally in non-polar organic solvent such as toluene, was carried out about 6 hours to about 10 hours preferred about 8 hours at about-80 ℃ to about room temperature.
The compound of formula I of the present invention can be used to treat and variously is reduced to the memory machine dysfunction of feature with choline function, as presenile dementia.Compound of the present invention is favourable, because its toxicity is littler than similar compound known in the art, and than these similar compounds the brain acetylcholine esterase is more had special efficacy.In addition, 6-O-demethylation ester of the present invention and carbonic acid ester derivative can decompose generation 6-O-demethylation lycoremine-a kind of known acetylcholinesterase depressant.
This availability is by these compound acetylcholine esterase inhibitions, thereby the ability that increases acetyl choline content in the brain obtains proof.
The ability of acetylcholine esterase inhibition is pressed the spectrphotometric method for measuring (Biochem.pharmacol.7,88(1961)) of Ellman etc.The result one of the result of some compound acetylcholine esterase inhibition of the present invention and reference compound acetylcholine esterase inhibition is listed in the table I.
The table I
This availability also can pass through the ability of these compounds of mensuration recovery choline function shortage memory in escaping dark test (Dark Avoidance Assay) and determine.In this test, remember the unhappy ability that stimulates 24 hours build-in test mouse.A mouse is inserted one to be contained in the chamber of camera bellows; With strong vehement light it is driven in the camera bellows, in camera bellows, impose electric shock by the tinsel on the base plate.This animal is taken out from test set, test them after 24 hours again and remember the ability that shocks by electricity.
Applied before animal enters test cabinet first if scopolamine-a kind of is had the compound cholinolytic function, that can cause hypomnesis, then this animal reenters camera bellows in the built-in test chamber after 24 hours immediately.Interrupt the effect of scopolamine with a kind of activity test compound, the bigger timed interval appearred in the result before reentering camera bellows.
Test-results represents with the percentage ratio of the interrupted treated animal of the effect of scopolamine, shows as in the built-in test chamber and reenters timed interval of the increase between the camera bellows.The dark test-results of the escape of some compound of the present invention is shown in the table II in the lump together with the result of reference compound.
The table II
The compound of the present invention of significant quantity can be applied to the patient by various different methods, for example with capsule or the dispenser of tablet per os, with sterile solution or suspension form administered parenterally, and in some cases with sterile solution form intravenous administration.Effectively final free alkali product itself can be with the form preparation and the dispenser of its pharmaceutically-acceptable acid addition, to reach stable, be convenient to crystallization, increase purpose such as solvability.
Useful acid comprises mineral acid in preparation pharmaceutically-acceptable acid addition of the present invention, example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid and perchloric acid, and organic acid, as tartrate, citric acid, acetate, succsinic acid, toxilic acid, fumaric acid and oxalic acid.
Active compound of the present invention can the per os dispenser, for example with a kind of inert diluent or with a kind of edible carrier, or they encapsulates, or they is pressed into tablet.In order to reach the purpose of per os dispenser, active compound of the present invention can be sneaked in the vehicle, uses with forms such as tablet, lozenge, capsule, elixir, suspension, syrup, wafer, chewing gums.These preparations should contain 0.5% active compound at least, but can change according to special shape, and can be aptly between per unit weight 5% is to about 70%.The amount of active compound should be enough to obtain suitable dose in this composition.The preferred present composition and preparation should be prepared into and contain 1.0-200 milligram active compound in the per os dose unit sample.
Tablet, pill, capsule, lozenge etc. also can contain following ingredients: tackiness agent such as Microcrystalline Cellulose, tragacanth gum or gelatin, vehicle such as starch or lactose, disintegrating agent and alginic acid, Primogel. W-Gum etc., lubricant such as Magnesium Stearate or Sterotex, glidant such as colloid silica, with sweetening agent such as sucrose or asccharin, or seasonings such as peppermint, wintergreen oil or the agent of orange flavor.When the dose unit sample is capsule, except that above types of materials, can contain liquid carrier such as fatty oil.Other dose unit samples can contain other different substancess of improvement dosage sample outward appearance, as coating.Therefore, tablet or pill can be coated with carbohydrate, lac or other intestines undercoat agent.Syrup removes the active ingredient beyond the region of objective existence can contain sucrose as sweetening agent and certain sanitas, dyestuff, tinting material and condiment.The material that is used to prepare these different preparations should be medicinal pure, and nontoxic under usage quantity.
For reaching parenteral dispenser purpose, active compound of the present invention can mix in solution or the suspension.These preparations should contain at least 0.1% active compound, but can change between 0.5 of its weight～about 30%.The amount of active compound should be enough to obtain suitable dose in this kind composition.The preferred present composition and preparation should be prepared into the parenteral dose unit and contain 0.5～100 milligram of active compound.
This solution or suspension also can comprise following composition: sterile diluent such as water for injection, salt brine solution, fixed oil, polyoxyethylene glycol, glycerine, propylene glycol or other synthetics, antiseptic-germicide such as benzylalcohol or methylParabens, oxidation inhibitor such as xitix or sodium bisulfite, sequestrant such as ethylenediamine tetraacetic acid (EDTA), buffer reagent such as acetate, Citrate trianion or phosphoric acid salt, and tension regulator such as sodium-chlor or glucose.The multiple flask for medicinal preparations of parenteral can be a glass or plastic.
Following table III and embodiment will further specify the present invention, but limit the present invention anything but.The table III has been listed typical compound of the present invention.Unless refer else, fusing point is the fusing point of hydrochloride.And then show III, described the preparation of representative compounds of the present invention.
*The m.p.220-222(literature value)
aBe separated into free alkali
Embodiment 1
6-O-demethylation lycoremine
With 0.57ml(0.48g) sulfur alcohol is added under nitrogen atmosphere in the 20ml of-40 ℃ of stirrings anhydrous DMF solution.Mixture stirs several minutes down at-40 ℃ to-30 ℃, slowly adds butyllithium (BuLi) the hexane solution of 2.84ml 2.5M then under-40 ℃ to-50 ℃ with syringe.In 15 minutes, solution is heated to room temperature then, under aspirator vacuum, is heated to 50 ℃, be cooled to 30 ℃ again.In this solution, add the solution of 0.57g lycoremine in the 5.7ml dry DMF.Stirred this solution 2 hours down at 95-100 ℃, stirred 3 hours down at 100-105 ℃ subsequently, it is cooled to room temperature, and is condensed into oil.This oil is dissolved in the chloroform, uses NH
4The Cl jolting, and use N
aHCO
3Aqueous solution furnishing alkalescence is used CHCl
3Extract four times.Use NH then
4OH transfers to 9-10 to water layer PH, uses chloroform extraction again four times.Use N
A2SO
4The organic extract liquid of dry mixed filters and is condensed into oil.This oil is dissolved in the 5% methyl alcohol/chloroform of the degassing, flash chromatography on silica gel with homogeneous solvent system wash-out, is used 10% methyl alcohol/chloroform wash-out earlier then, obtains a beige solid.This material is dissolved in acetone, and the crystallization of spending the night obtains the 0.298g(6-O-demethylation) lycoremine, m.p.225-229 ℃.
Analyze:
Analyze:
C
16H
19NO
3Calculated value: 70.31%C 7.01%H 5.12%N
Measured value: 70.14%C 7.29%H 4.96%N
Embodiment 2
6-O-demethylation-[3-O, two (1-methylethyl) carbonyls of 6-O-] lycoremine hydrochloride hydrate
4-Dimethylamino pyridine (1.2g) is added to 6-O-demethylation lycoremine (0.5g) in the cold soln of 125ml methylene dichloride, adds isobutyric anhydride (1.0ml) then in the solution of 5.0ml methylene dichloride., at room temperature stirred then 1 hour after 1 hour 0 ℃ of stirring, this solution evaporation is become oil, oil is dissolved in the ethyl acetate, anhydrous sodium sulfate drying is used in water, yellow soda ash, saturated nacl aqueous solution washing then.Filter the back and steam to desolventize and obtain oil (0.7g), should oil through HPLC on silicagel column with 10% ethanol/methylene wash-out, obtain a yellow viscous oil (0.5g), this oil is dissolved in ether, with ether-HCL PH is transferred to 1.Collect the precipitation and the drying that produce, obtain pale solid, this solid recrystallization in methanol (1: 10) obtains the 0.35g product, m.p.225 ℃ (decomposition).
Analyze:
C
24H
3NO
5HClH
2The meter 61.59%C 7.32%H 2.99%N of O
The calculation value:
Measured value: 61.53%C 7.34%H 2.97%N
Embodiment 3
6-O-demethylation-6-O-(tertiary butyl carbonyl) lycoremine hydrochloride
With 0.74ml(0.68g) trimethyl acetic anhydride, be that the 1.0g6-O-demethylation lycoremine that add to stir of 45mg4-dimethyl aminopyridine is in the suspension of 6.5ml chloroform then.Stirring at room mixture 4 hours.This solution injection has been filled on the flash chromatography post of 3% methyl alcohol/chloroform,, used 5% methyl alcohol/chloroform wash-out then with homogeneous solvent system wash-out.Mix the fraction that contains product and also concentrate, obtain a white solid (quantitatively output).This material of recrystallization in cyclohexane filters, and drying is dissolved in ether, and hydrochloride precipitates behind adding ether-HCl.This salt of filtering separation and drying obtain 0.421g6-O-demethylation-6-O-(tertiary butyl carbonyl) the lycoremine hydrochloride, m.p.250-251 ℃.
Analyze:
C
21H
27NO
4HCl calculated value: 64.03%C 7.16%H 3.56%N
Measured value: 63.99%C 7.21%H 3.44%N
Embodiment 4
6-O-demethylation-[3-O, 6-O-two (ethyl carbonyl)] lycoremine hydrochloride
4-Dimethylamino pyridine (3.5g) is added 6-O-demethylation lycoremine (1.5g) in the cold soln of 100ml methylene dichloride, slowly add propionic anhydride (2.4ml) then in the solution of 10ml methylene dichloride., steam the back mixture and obtain yellow oil after 1 hour in stirring at room, this oil is dissolved in the ethyl acetate.Water, sodium carbonate solution, saturated nacl aqueous solution wash this solution, use anhydrous MgSO then
4Dry.Filter the back and steam to desolventize and obtain yellow oil 2.0g, this oil by flash chromatography on silicagel column with 5% ethanol/methylene wash-out.Mix the expectation fraction, evaporate a yellow viscous oil 1.8g.This oil is dissolved in the ether, PH is adjusted to 1 with ether-HCl.Collect the precipitation and the drying that produce, obtain 1.8 products, m.p.170-172 ℃.
Analyze:
C
22H
27NO
5The calculated value of HCl: 62.62%C 6.69%H 3.32%N
Measured value: 62.19%C 6.65%H 3.16%N
Embodiment 5
6-O-demethylation-6-O-(ethanoyl) lycoremine hydrochloride
With the 0.35ml diacetyl oxide, being the 45.5mg DMAP that is dissolved in the 0.5ml chloroform then adds the 1.02g6-O-demethylation lycoremine that stirs in the suspension of 6.0ml chloroform with syringe.Stirred this suspension under the room temperature 3.5 hours, and then it was filtered on the flash chromatography post, this post is filled with the silica gel that immerses 5% methyl alcohol/chloroform, and with homogeneous solvent system wash-out.Mix the fraction contain product and concentrate obtaining a yellow oil, should oil crystallization in ether, obtain the 0.44g white solid.Solid is dissolved in the chloroform, with the ether dilution, adds ether-HCl and makes the hydrochloride precipitation, obtains 0.47g6-O-demethylation-6-O-(ethanoyl) the lycoremine hydrochloride, recrystallization in acetonitrile, m.p.244-246 ℃ (decomposition).
Analyze:
C
18H
21NO
4HCl calculates 61.45%C 6.30%H 3.98%N
Value:
Measured value: 60.97%C 6.34%H 3.86%N
Embodiment 6
6-O-demethylation-3-O, two (ethanoyl) lycoremine hydrochlorides of 6-O-
With 4-Dimethylamino pyridine (4.6g), be that diacetyl oxide (2.3ml) solution adds 6-O-demethylation lycoremine (2.0g) in the cold soln of 75ml methylene dichloride then.After the stirring at room 5 hours, through HPLC on silicagel column with 3% this solution of ethanol/methylene wash-out.Mix the expectation fraction, evaporation obtains a yellow viscous oil (2.1g) then.This oil samples of 0.5g is dissolved in the methyl alcohol, and being acidified to PH with ether-HCl then is 1; Dilute with ether then.Collect the white precipitate and the drying that produce, obtain 0.4g, m.p.142 ℃ (decomposition).
Analyze:
C
20H
23NO
5HCl calculated value: 60.99%C 6.14%H 3.56%N
Measured value: 60.78%C 6.08%H 3.48%N
Embodiment 7
6-O-demethylation-3-O-(ethanoyl) lycoremine hydrochloride
The 5ml saturated sodium bicarbonate solution is added 1.5g 6-O-demethylation-3-O, and two (ethanoyl) lycoremines (embodiment 6) of 6-O-are in the solution of 30ml methyl alcohol.After the stirring at room 20 hours, in mixture impouring 100ml water, stirred 5 minutes, use dichloromethane extraction then.Water, saturated Nacl solution washing dichloromethane layer are used anhydrous MgSO then
4Dry.Steam to desolventize after filtering and obtain a brown solid, 1.35g, 215 ℃ of decomposition.This material is dissolved in the methyl alcohol, and being acidified to PH with ether-HCl then is 1; Dilute with ether subsequently.Collect the white precipitate and the drying that produce, obtain the 1.0g product, m.p.162 ℃ (decomposition).
Analyze:
C
18H
21NO
4HCl calculated value: 61.44%C 6.30%H 3.98%N
Measured value: 61.53%C 6.56%H 4.21%N
Embodiment 8
6-O-demethylation-[3-O, 6-O-two (tertiary butyl carbonyl)] lycoremine hydrochloride
With 4-Dimethylamino pyridine (3.5g), be that trimethyl acetic anhydride (3.8ml) is added to 6-O-demethylation lycoremine (1.5g) in the cold soln of 100ml methylene dichloride in the solution of 10ml methylene dichloride then.After the stirring at room 1 hour, this solution obtains a yellow oil after the steaming.Water, sodium carbonate solution, saturated nacl aqueous solution wash the solution of this oil and ethyl acetate, use anhydrous MgSO then
4Dry.After the filtration, evaporating solvent obtains a yellow solid, this solid through flash chromatography on silicagel column with 2% ethanol/methylene wash-out.Mix the expectation fraction, evaporate a white solid 1.6g, m.p.117-119 ℃.With ether-HCl the solution of this solid and ether being transferred to PH is 1, collects the white precipitate and the drying that produce, obtains the 1.4g product, m.p.265 ℃ (decomposition).
Analyze:
C
26H
35NO
5HCl calculated value: 65.33%C 7.59%H 2.93%N
Measured value: 64.85%C 7.67%H 2.68%N
Embodiment 9
6-O-demethylation-6-O-(third-2-base-oxygen carbonyl) lycoremine hydrochloride
With triethylamine (0.8ml), be that (solution in the 1.0M toluene 5.5ml) is added to 1.5g6-O-demethylation lycoremine in the cold soln of 60ml methylene dichloride to carbonochloridic acid isopropyl ester solution then.0 ℃ is stirred after 1 hour stirring at room mixture 20 hours down.Mixture is added on the quick silicagel column, with 10% ethanol/methylene wash-out.Mix the expectation fraction, evaporate a yellow viscous oil 0.5g.This oil is dissolved in the methanol (1: 10), and being acidified to PH with ether-HCl then is 1.Collect the white precipitate and the drying that produce, obtain the 0.4g product, m.p.218 ℃ (decomposition).
Analyze:
C
20H
25NO
5HCl calculated value: 60.67%C 6.62%H 3.54%N
Measured value: 61.15%C 6.56%H 3.44%N
Embodiment 10
6-O-demethylation-3-O-(third-2-base carbonyl)-and 6-O-(tertiary butyl carbonyl) the lycoremine hydrochloride hydrate
With 4-Dimethylamino pyridine (0.9g), be that isobutyric anhydride solution (1.2ml is in the 10ml methylene dichloride) is added to 6-O-demethylation-6-O-(tertiary butyl carbonyl then) lycoremine (embodiment 9) is (2.6g) in the solution of 100ml methylene dichloride.After the stirring at room 20 hours, mixture is added on the silicagel column, through HPLC with 3% ethanol/methylene wash-out.Mix the expectation fraction, evaporate then a pure viscous crude (2.0g).To transfer to PH be 1 to diethyl ether solution that should oil with ether-HCl.Collect the white precipitate and the drying that produce, obtain the 1.8g product, m.p.248 ℃ (decomposition).
Analyze:
C
25H
33NO
5HCl calculated value: 62.29%C 7.53%H 2.91%N
Measured value: 62.42%C 7.32%H 2.76%N
Embodiment 11
6-O-demethylation-6-O-(benzoyl) lycoremine
0.44ml 1.8-diazabicyclo [5.4.0] undecane-7-alkene is added in the suspension of 0.8g6-O-demethylation lycoremine, 8ml chloroform and 0.72g benzoyl oxide of stirring.Stirring at room mixture 4 hours, impouring is with on the flash chromatography post that is dipped in the silica gel filling in 3% methyl alcohol/chloroform then.Earlier use the homogeneous solvent system, use 5% methyl alcohol/this post of chloroform wash-out then.Mix the fraction that contains product, concentrate and obtain oil, the crystallization in ether of this oil obtains 0.45g6-O-demethylation-6-O-benzoyl lycoremine, m.p.144-145 ℃.
Analyze:
C
23H
23NO
4Calculated value: 73.19%C 6.14%H 3.71%N
Measured value: 73.29%C 6.11%H 3.79%N
Embodiment 12
6-O-demethylation-6-O-(tertiary butyl carbonyl)-and 3-O-(n-heptyl carbonyl) lycoremine half hydrochloride hydrate
With 4-Dimethylamino pyridine (1.0g), to be n-caprylic acid acid anhydride (2.4ml) then add 2.6g6-O-demethylation-6-O-(tertiary butyl carbonyl in the solution of 10ml methylene dichloride) lycoremine (embodiment 11) is in the cold soln of 100ml methylene dichloride.After the stirring at room 20 hours, through HPLC on silicagel column with 3% this mixture of ethanol/methylene wash-out.Mix the expectation fraction, evaporation obtains pure viscous crude then, and its cooling curing is obtained the 3.0g white solid, and m.p. is 27 ℃.This solid is dissolved in methyl alcohol, the PH of solution is transferred to 1, dilute with ether then with ether-HCl.Collect the white precipitate and the drying that produce, obtain the 2.0g product, m.p. is 185-187 ℃.
Analyze:
C
29H
41NO
5HCl0.5H
2O calculates 65.83%C 8.19%H 2.65%N
Value:
Measured value: 65.98%C 8.13%H 2.65%N
Embodiment 13
6-O-demethylation-3-O, two (n-heptyl carbonyl) lycoremine half hydrochloride hydrates of 6-O-
With 4-Dimethylamino pyridine (3.5g), be that caprylic anhydride (5.6ml) is added to 1.5g6-O-demethylation lycoremine in the cold soln of 75ml methylene dichloride in the solution of 25ml methylene dichloride then.Stirring at room 20 hours after HPLC on silicagel column with 3% ethanol/methylene elution mixture.Mix the expectation fraction, evaporation obtains a yellow viscous oil 2.3g then.This oil is dissolved in the methyl alcohol, with ether-HCl PH is transferred to 1, dilutes with ether then.Collect the white precipitate and the drying that produce, obtain the 2.0g product, m.p. is 215 ℃ (decomposition).
Analyze:
C
32H
47NO
5·HCl· 67.28%C 8.65%H 2.45%N
0.5H
2The O calculated value:
Measured value: 67.01%C 8.91%H 2.25%N
Embodiment 14
6-O-demethylation-3-O, two (tert-butoxycarbonyl) lycoremine hydrochlorides of 6-O-
With 4-Dimethylamino pyridine (2.3g), be that hydrogen-carbonate di tert butyl carbonate (2.9ml) is added in the cold soln of 6-O-demethylation lycoremine (1.0g is in the 50ml methylene dichloride) in the solution of 20ml methylene dichloride then.After the stirring at room 40 hours, through HPLC on silicagel column with 3% ethanol/methylene elution mixture.Mix the expectation fraction, evaporate then a yellow viscous oil 1.3g.This oil is dissolved in the methyl alcohol, transfers PH to 1 with ether-HCl, dilutes with ether then.Collect the white precipitate and the drying that produce, obtain 1.2 products, m.p. is 154 ℃ (decomposition).
Analyze:
C
26H
35NO
7HCl calculated value: 61.23%C 7.12%H 2.75%N
Measured value: 60.83%C 7.10%H 2.72%N
Embodiment 15
7-bromo-6-O-demethylation lycoremine
7-bromo-6-O-demethylation lycoremine
With 0.34ml(1.05g) bromine is added drop-wise to the 1.38ml(0.966g of stirring) TERTIARY BUTYL AMINE in 36ml at-20 ℃ to the solution of-30 ℃ of azeotropic dry toluene, so that temperature maintenance is at-20 ℃ to-30 ℃.Cool off this solution then to-70 ℃ to-75 ℃, slowly add 3.0g6-demethylation lycoremine in the solution of 15mlDMF, so that temperature does not rise to more than-70 ℃.-70 ℃ to-78 ℃ following stirred solutions 2 hours, in 6 hours, slowly be heated to room temperature subsequently.Solution is cooled to 0 ℃ again, impouring ice/N
aHCO
3In/the water, use chloroform extraction.Aqueous portion is saturated with NaCL, uses chloroform extraction three times.Chloroform extract Na
2SO
4Oil is filtered and be condensed into to drying, should oil with the HPLC purifying, and use instrument to be Water Prep 500 Imstrument, first with 3% methyl alcohol/chloroform wash-out, use 5% methyl alcohol/chloroform wash-out then.Mix the pure fraction that contains product and also concentrate, obtaining 1.83g(is 47.3% based on 6-demethylation lycoremine, is 78.9% based on bromine, limiting reagent) product.Crystallization obtains analytically pure 7-bromo-6-O-demethylation lycoremine in acetone, and m.p. is 138-141 ℃.
Analyze:
C
16H
18BrNO
3Calculated value: 54.56%C 5.15%H 3.98%N
Measured value: 54.62%C 5.50%H 3.61%N
Embodiment 16
7-bromo-6-O-demethylation-6-O-(tertiary butyl carbonyl) lycoremine hydrochloride
With 0.37ml(0.34g) the PIVALIC ACID CRUDE (25) acid anhydride, be then 23mgDMAP be added to stirring, by about 0.528g7-bromo-6-O-demethylation lycoremine and 93.2mg 6-O-demethylation lycoremine in the suspension that the mixture of 4ml chloroform forms.Stirring at room mixture 5 hours.In the flash chromatography post of solution impouring,, use 5% methyl alcohol/chloroform wash-out then with same solvent system wash-out with 3% methyl alcohol/chloroform filling.Mix the fraction that contains product, be condensed into white solid.This material is dissolved in ether, and decant adds ether-HCl and makes the hydrochloride precipitation.This material of filtering separation, and, obtain 0.315g 7-bromo-6-O-demethylation-6-O-(tertiary butyl carbonyl 80 ℃ of vacuum-dryings) lycoremine, m.p. is 275-278 ℃.
Analyze:
C
21H
26BrNO
4Calculated value: 53.35%C 5.76%H 2.96%N
Measured value: 53.37%C 5.41%H 2.79%N
Embodiment 17
6-O-demethylation-6-O-(ethyl carbonyl) lycoremine hydrochloride
With the 0.47ml propionic anhydride, be that the DMAP that 45.2mg is dissolved in the 0.5ml chloroform is added to the 1.00g6-O-demethylation lycoremine of stirring in the suspension of 6.5ml chloroform then.Stirring at room should the suspension liquid-liquid, is filled on the flash chromatography post that is filled with silica gel and 3% methyl alcohol/chloroform, with same solvent system wash-out, uses 5% methyl alcohol/chloroform wash-out then.Mix the fraction that contains product, and concentrate, obtain a yellow solid.Recrystallization obtains 0.70g in cyclohexane.Use ether-HCl to make the hydrochloride precipitation, obtain 0.74g6-O-demethylation-6-O-(ethyl carbonyl) the lycoremine hydrochloride, this salt recrystallization in acetonitrile, m.p.221-223 ℃.
Analyze:
C
19H
23NO
4HCl calculated value: 62.38%C 6.61%H 3.83%N
Measured value: 62.32%C 6.67%H 3.89%N
Embodiment 18
6-O-ethanoyl-7-bromo-6-O-demethylation lycoremine hydrochloride
With 0.227ml(0.245g) diacetyl oxide is that the 29.6mg4-Dimethylamino pyridine is added to the 0.851g7-bromo-6-demethylation lycoremine of stirring in the solution of 2ml chloroform then.This solution of stirring at room 3 hours.Then in the quick silicagel column of mixture impouring with the silica gel filling of immersing 3% methyl alcohol/chloroform.With same solvent system wash-out, use 5% methyl alcohol/chloroform wash-out then.Mix the pure fraction contain product, be condensed into oil and in ether crystallization obtain the 0.455g clear crystal.This material is dissolved in chloroform/ether, adds ether-HCl and make the hydrochloride precipitation, filtering separation is also dry, obtains 335mg6-O-ethanoyl-7-bromo-6-O-demethylation lycoremine hydrochloride, and m.p. is 236-238 ℃.
Analyze:
C
18H
20BrNO
4Calculated value: 50.19%C 4.91%H 3.25%N
Measured value: 49.83%C 4.65%H 3.09%N
Embodiment 19
6-O-demethylation-6-O-(methoxycarbonyl) lycoremine hydrochloride
With 4-Dimethylamino pyridine (0.7g), be that coke dimethyl phthalate (0.6ml) is added to 6-O-demethylation lycoremine (1.5g) in the cold soln of 60ml methylene dichloride in the solution of 10ml methylene dichloride then.After the stirring at room 4 hours, through HPLC on silicagel column with 3% this solution of ethanol/methylene wash-out.Mix the expectation fraction, evaporate then a pure viscous crude 1.0g.This oil is dissolved in the methyl alcohol, and being acidified to PH with ether-HCl then is 1, dilutes with ether again.Collect the white precipitate and the drying that produce, obtain the 1.0g product, 195 ℃ of decomposition.
Analyze:
C
18H
21NO
5HCl calculated value: 58.77%C 6.03%H 3.81%N
Measured value: 58.54%C 6.20%H 3.74%N
Embodiment 20
6-O-demethylation-6-O-(ethoxycarbonyl) lycoremine hydrochloride
With 4-Dimethylamino pyridine (0.7g), be that diethylpyrocarbonate (0.8ml) is added to 6-O-demethylation lycoremine (1.5g) in the cold soln of 60ml methylene dichloride in the solution of 10ml methylene dichloride then.After the stirring at room 4 hours, through HPLC on silicagel column with 3% this solution of ethanol/methylene wash-out.Mix the expectation fraction, evaporate then a white solid, 1.8g, m.p.139-141 ℃.This material is dissolved in methyl alcohol, and being acidified to PH with ether-HCl then is 1, dilutes with ether again.Collect the white precipitate and the drying that produce, obtain the 1.3g product, 208 ℃ of decomposition.
Analyze:
C
19H
23NO
5HCl calculated value: 59.76%C 6.33%H 3.67%N
Measured value: 59.74%C 6.32%H 3.44%N
Embodiment 21
6-O-demethylation-6-O-(tert-butoxycarbonyl) lycoremine hydrochloride
With 4-Dimethylamino pyridine (0.7g), be that Di-tert butyl pyrocarbonate (1.3ml) is added to 6-O-demethylation lycoremine (1.5g) in the cold soln of 60ml methylene dichloride in the solution of 10ml methylene dichloride then.After the stirring at room 4 hours, through HPLC on silicagel column with 3% this solution of ethanol/methylene wash-out.Mix the expectation fraction and evaporate a white solid, 1.9g, m.p.147-149 ℃.This solid is dissolved in methyl alcohol, and being acidified to PH with ether-HCl is 1, dilutes with ether again.Collect the white precipitate and the drying that produce, obtain the 1.3g product, 237 ℃ of decomposition.
Analyze:
C
21H
27NO
5HCl calculated value: 61.53%C 6.88%H 3.42%N
Measured value: 61.62%C 6.49%H 3.36%N
Embodiment 22
6-O-demethylation-6-O-(n-heptyl carbonyl) lycoremine hydrochloride
The anhydrous THF of 13.5ml is added to 0.80g(2.93mmol) 6-O-demethylation lycoremine and 0.82g(5.92mmol) in the mixture of ground salt of wormwood.This suspension is cooled to 0 ℃, adds 1.10ml(3.70mmol afterwards) caprylic anhydride.Reaction mixture stirred 0.5 hour down in 0 ℃, at room temperature stirred again 3 hours, afterwards with suspension filtered to the flash chromatography post that is filled with silica gel and 3% methyl alcohol/chloroform, with same solvent system wash-out, use 5% anhydrous methanol/chloroform wash-out then.Mix the pure fraction that contains product and also concentrate, obtain 0.88g(2.20mmol; 75.3%) oily free alkali.This oil is dissolved in the ether, adds ether-HCl and is settled out hydrochloride, gets 0.51g6-O-demethylation-6-O-(n-heptyl carbonyl) the lycoremine hydrochloride, m.p.158-161 ℃.
Analyze:
C
24H
33NO
4HCl calculated value: 66.12%C 7.86%H 3.21%N
Measured value: 66.01%C 7.75%H 3.07%N
Embodiment 23
6-O-demethylation-6-O-(normal-butyl carbonyl) lycoremine hydrochloride
With 0.45g(3.66mmol) the 4-Dimethylamino pyridine solution that is dissolved in the 6.0ml chloroform is added to the 1.00g(3.6mmol of stirring with syringe) 6-O-demethylation lycoremine is dissolved in the suspension of 10.0ml chloroform, adds 0.69ml(3.49mmol with syringe then) valeric anhydride (being dissolved in the 4.0ml chloroform).Stirring at room reaction mixture 0.5 hour injects it on the flash chromatography post of filling with silica gel and 3% methyl alcohol/chloroform then, with same solvent system wash-out, uses 5% methyl alcohol/chloroform wash-out then.Mix suitable fraction and be condensed into yellow pure oil.This oil is dissolved in ether, adds ether-HCl and is settled out hydrochloride, obtains 0.73g(1.85mmol; 51%) lycoremine hydrochloride 6-O-demethylation-6-O-(normal-butyl carbonyl), m.p.208-210 ℃.
Analyze:
C
21H
28NO
4HCl calculated value: 64.03%C 7.16%H 3.56%N
Measured value: 63.91%C 7.25%H 3.48%N
Embodiment 24
6-O-demethylation-6-O-(n-pentyl carbonyl) lycoremine hydrochloride
With 0.45g(3.67mmol) 4-Dimethylamino pyridine (being dissolved in the 4.0ml chloroform) is added to the 1.00g(3.66mmol of stirring with syringe) 6-O-demethylation lycoremine in the solution of 10.0ml chloroform, add 0.80ml(0.74mmol with syringe then) acid anhydrides (being dissolved in the 6.0ml chloroform).Stirring at room mixture 3.5 hours on the flash chromatography post of its impouring with silica gel and 3% methyl alcohol/chloroform filling, with same solvent system wash-out, is used 5% methyl alcohol/chloroform wash-out then.Mix suitable fraction and be concentrated into yellow oil, heavy 1.26g(3.39mmol; 92%).This oil is dissolved in the ether, is settled out hydrochloride with ether-HCl, obtains 0.77g(1.87mmol; 51%) lycoremine hydrochloride 6-O-demethylation-6-O-(n-pentyl carbonyl), m.p.212-215 ℃.
Analyze:
C
22H
29NO
4HCl calculated value: 64.78%C 7.41%H 3.43%N
Measured value: 64.66%C 7.25%H 3.37%N
Embodiment 25
The basic just carbonyl of 6-O-demethylation-6-O-() lycoremine hydrochloride
With 0.45g(3.69mmol) 4-Dimethylamino pyridine (being dissolved in the 4.0ml chloroform) is added to the 1.00g(3.66mmol of stirring with syringe) 6-O-demethylation lycoremine is in the solution of 10.0ml chloroform, stirring at room added 0.91ml(3.47mmol with syringe after 20 minutes) positive heptylic anhydride (being dissolved in the 6.0ml chloroform).Stirring at room reaction mixture 0.5 hour on the flash chromatography post of its impouring with silica gel and 3% methyl alcohol/chloroform filling, with same solvent system wash-out, is used 5% methyl alcohol/chloroform wash-out then.Mix and contain the pure fraction of product and be concentrated into yellow oil, heavy 114g(2.95mmol; 81%).This oil is dissolved in the ether, is settled out hydrochloride with ether-HCl, obtains 0.74g(1.75mmol; 48%) the lycoremine hydrochloride basic just carbonyl of 6-O-demethylation-6-O-(), m.p.178-180 ℃.
Analyze:
C
23H
31NO
4HCl calculated value: 65.47%C 7.64%H 3.32%N
Measured value: 65.18%C 7.88%H 3.18%N
Embodiment 26
6-O-demethylation-3-O-[2-(methyl) butane-2-base-oxygen base carbonyl]-the 6-O-(ethanoyl) the lycoremine hydrochloride hydrate
With hydrogen-carbonate two tert-pentyl ester (2.2ml, 0.009mol) be added to 6-O-demethylation-6-O-(methyl carbonyl in the drips of solution of 10ml methylene dichloride) (embodiment 5 for lycoremine, 2.8g 0.009mol) (1.1g is 0.009mol) in the cold soln of 80ml methylene dichloride with the 4-Dimethylamino pyridine.After the stirring at room 20 hours, through HPLC on silicagel column with 3% this mixture of ethanol/methylene wash-out.Mix the expectation fraction and be evaporated to pure viscous crude, 2.7g(69%).The 0.4g oil samples is dissolved in methyl alcohol, and transferring PH with ether-HCl is 1, dilutes with ether then.Collect the white precipitate and the drying that produce, obtain 0.3g(70%) product-colorless solid, m.p.178-180 ℃ (decomposition).
Analyze:
C
24H
31NO
6HClH
2O calculated value: 59.56%C 7.08%H 2.89%N
Measured value: 59.84%C 7.01%H 3.02%N
Embodiment 27
6-O-demethylation-3-O-[2-(methyl) butane-2-base oxygen base carbonyl] lycoremine
With the saturated N of 5ml
aHCO
3The aqueous solution is added to 6-O-demethylation-3-O-[2-(methyl) butane-2-base oxygen base carbonyl]-the 6-O-(ethanoyl) (embodiment 26, and 2.0g is 0.0047mol) in the solution of 25ml methyl alcohol for lycoremine.
After the stirring at room 4 hours, in the mixture impouring 100ml water, stirred 5 minutes; Use dichloromethane extraction (3 * 100ml) then.Anhydrous MgSO is used in dichloromethane solution water, saturated nacl aqueous solution washing
4Dry.
After the filtration, filtrate is added in the silicagel column, through HPLC with 5% ethanol/methylene wash-out.Mix the expectation fraction and be evaporated to pale solid, it is developed with hot ether; Obtain white solid product, 0.4g(22%), m.p.175 ℃ (decomposition).
Analyze:
C
22H
29NO
5Calculated value: 68.19%C 7.54%H 3.62%N
Measured value: 67.99%C 7.50%H 3.52%N
Embodiment 28
3-O-[2-methylbutane-2-base oxygen base carbonyl] the lycoremine hydrochloride hydrate
(2.4ml, (3.0g, 0.01mol) (1.2g is 0.01mol) in the cold soln of 80ml methylene dichloride with the 4-Dimethylamino pyridine 0.01mol) to be added to lycoremine in the drips of solution of 15ml methylene dichloride with the hydrogen-carbonate di tert butyl carbonate.
After the stirring at room 48 hours, mixture through HPLC on silicagel column with 3% ethanol/methylene wash-out.Mix the expectation fraction and evaporate obtaining a pure viscous crude, 1.1g(28%).This oil is dissolved in the methyl alcohol, transfers PH to 1 with ether-HCl, dilutes with ether then.Collecting precipitation is also dry, obtains 0.70g(15%) the colorless solid product, m.p.167 ℃ (decomposition).
Analyze:
C
23H
34NO
5H
2OHCl calculated value: 60.58%C 7.52%H 3.07%N
Measured value: 60.68%C 7.28%H 3.48%N
Embodiment 29
6-O-demethylation-6-O-[(ethoxycarbonyl) methyl] lycoremine
With 5.00g(18.29mmol) 6-O-demethylation lycoremine is in 17.5mlN, the solution of dinethylformamide was added to 0.70g(17.45mmol in 5-10 minute) sodium hydride (in 60% mineral oil) is in the room temperature suspension of 12.5ml tetrahydrofuran (THF).This mixture of cooling in ice bath, and stirred 20 minutes at 0 ℃ slowly adds 2.03ml(18.29mmol afterwards) ethyl bromoacetate is in the solution of 5ml tetrahydrofuran (THF), stirring at room 1 hour.Twice of chloroform extraction will also be used in the gained mixture impouring frozen water.Mix organic layer, use dried over sodium sulfate, filter and the concentrated brown oil that obtains.This oil is dissolved in the chloroform, carries out stratographic analysis,, use 5% methyl alcohol/chloroform wash-out then with 2% methyl alcohol/chloroform wash-out with Waters Prep 500 HPLC.Mix the pure fraction that contains product and concentrate and obtain reddish oil-6-O-demethylation-6-O-(ethoxycarbonyl) the methyl lycoremine, 2.60g.
Analyze:
C
20H
25NO
5Calculated value: 66.84%C 7.01%H 3.90%N
Measured value: 66.56%C 6.86%H 3.85%N
Embodiment 30
6-O-demethylation-6-O-[2-(methyl) butane-2-base-oxygen carbonyl] the lycoremine hydrochloride
(0.7ml, (2.0g, 0.007mol) (0.85g is 0.007mol) in the cold soln of 70ml methylene dichloride with the 4-Dimethylamino pyridine 0.007mol) to be added to 6-O-demethylation lycoremine in the drips of solution of 10ml methylene dichloride with hydrogen-carbonate two tert-pentyl esters.
After the stirring at room 8 hours, mixture is added on the silicagel column through HPLC with 3% methyl alcohol/chloroform wash-out.Vacuum-evaporation expectation fraction.Obtain white solid, 2.2g(85%), m.p.129-130 ℃.
This material is dissolved in the ether, transfers PH to 1, obtain white solid with ether-HCl, 1.8g(63%), m.p.205 ℃ (decomposition).
Analyze:
C
22H
29NO
5HCl calculated value: 62.33%C 7.13%H 3.34%N
Measured value: 62.49%C 7.16%H 3.35%N
Embodiment 31
6-O-demethylation-6-O-(2,6-xylyl carbonyl) the lycoremine hydrochloride
With 2,6-dimethylamino benzophenone acyl chlorides (1.2g, 0.007mol) in the drips of solution of 10ml methylene dichloride be added to 6-O-demethylation lycoremine (2.0g, 0.007mol), triethylamine (1.0ml, 0.007mol) and 4-Dimethylamino pyridine (0.01g) in the cold soln of 70ml methylene dichloride.
After the stirring at room 20 hours, mixture is added in the silicagel column, through HPLC with 3% ethanol/methylene wash-out.Mix expectation fraction and vacuum-evaporation, get a white solid, 2.7g(95%), m.p.159-161 ℃.
The sample of this material of 1.5g is dissolved in the ethyl acetate, and transferring PH with ether-HCl is 1, gets a white solid, 1.1g(81%), and m.p.207 ℃ (decomposition).
Analyze:
C
25H
27NO
4HCl calculated value: 67.94%C 6.39%H 3.17%N
Measured value: 67.58%C 6.63%H 3.11%N
Embodiment 32
6-O-demethylation-6-O-(2-tolyl carbonyl) lycoremine hydrochloride
With adjacent toluyl chlorine (0.9ml, 0.007mol) be added to 6-O-demethylation lycoremine (2.0g in the drips of solution of 10ml methylene dichloride, 0.007mol), (1.0g, 0.007mol) (0.01g is 0.0001mol) in the cold soln of 70ml methylene dichloride with the 4-Dimethylamino pyridine for triethylamine.
After the stirring at room 3 hours, mixture is added in the silicagel column through HPLC with 3% ethanol/methylene wash-out.Mix the expectation fraction and evaporate then, get a white solid, 1.7g(63%), m.p.148-150 ℃.
This solid ethyl acetate solution is transferred PH to 1 with ether-HCl, collects the white precipitate and the drying that produce, obtains 1.2g(40%) product, m.p.255 ℃ (decomposition).
Analyze:
C
24H
25NO
4HCl calculated value: 67.36%C 6.12%H 3.27%N
Measured value: 67.62%C 6.49%H 3.09%N
Embodiment 33
6-O-demethylation-6-O-(2,2-dimethyl propyl carbonyl) the lycoremine hydrochloride
With 0.55ml(3.67mmol) 1,8-diazabicyclo [5,4,0] undecane-7-alkene is added to the 1.00g(3.66mmol of stirring with syringe) 6-O-demethylation lycoremine is in the suspension of 10.00ml chloroform.Stirred the mixture in the ice bath 10-15 minute, and added 0.55ml(3.99mmol with syringe afterwards) tert.-butyl acetate.After adding suspension risen to room temperature and under this temperature, stirred 0.5 hour, inject 50ml refrigerative saturated sodium bicarbonate solution, use chloroform extraction.Add sodium-chlor in the water layer, use twice of chloroform extraction.Mix organic layer with dried over sodium sulfate, filter, concentrate yellow oil.This oil is dissolved in the chloroform, is filled on the flash chromatography post of filling with silica gel and 3% methyl alcohol/chloroform, earlier with same solvent system wash-out, uses 5% methyl alcohol/chloroform wash-out again.Mix suitable fraction and concentrated, obtain 0.61g(1.64mmol, 45%) white solid.This solid is dissolved in ether, adds ether-HCl and is settled out hydrochloride, obtains 6-O-demethylation-6-O-(2,2-dimethyl propyl carbonyl) the lycoremine hydrochloride, m.p.234-236 ℃ (decomposition).
Analyze:
C
22H
29NO
4HCl calculated value: 64.78%C 7.41%H 3.43%N
Measured value: 64.60%C 7.65%H 3.39%N
Embodiment 34
6-O-demethylation-6-O-[(2-methyl) pentane-2-base carbonyl] the lycoremine hydrochloride
With 0.75g(3.66mmol) 1,3-dicyclohexylcarbodiimide (being dissolved in the 0.7ml chloroform) is added to the 0.48g(3.67mmol of stirring) 2,2-dimethyl valeric acid adds 1.00g(3.66mmol then in the suspension of 2.5ml chloroform) 6-O-demethylation lycoremine (in the 2.0ml chloroform) and 0.45g(3.67mmol) 4-Dimethylamino pyridine (in the 0.2ml chloroform).Stirring at room suspension 6 hours is filled into it on the flash chromatography post of filling with silica gel and 3% methyl alcohol/chloroform then, with homogeneous solvent system wash-out, uses 5% methyl alcohol/chloroform wash-out then.Mix suitable fraction and concentrated, get 0.68g(1.78mmol, 49%) yellow oil.This oil is dissolved in the ether, adds ether-HCl and is settled out hydrochloride, obtains 6-O-demethylation-6-O-[[(2-methyl) pentane-2-yl] carbonyl] the lycoremine hydrochloride, m.p.254-256 ℃ (decomposition).
Analyze:
C
23H
31NO
4HCl calculated value: 65.47%C 7.64%H 3.32%N
Measured value: 65.60%C 7.61%H 3.32%N
Embodiment 35
6-O-demethylation-6-O-[2-(methyl) propyl group carbonyl] the lycoremine hydrochloride
With 0.44ml(2.94mmol) 1, the 0.80g(2.91mmol that 8-diazabicyclo [5,4,0] undecane-7-alkene add to stir with syringe) 6-O-demethylation lycoremine is in the suspension of 8ml chloroform.Cooling suspension is 10 minutes in ice bath, adds 0.38ml(3.12mmol with syringe afterwards) isoveryl chloride.Reaction mixture rises to room temperature, injects the refrigerative saturated sodium bicarbonate solution after stirring 2 hours under this temperature, uses chloroform extraction.Water layer is handled with sodium-chlor, and with twice of chloroform extraction.Mix the organic extract liquid dried over sodium sulfate, filter, and concentrated a yellow oil.This oil is dissolved in the chloroform, inhales to move on in the flash chromatography post of filling with the silica gel that is dipped in 3% methyl alcohol/chloroform, with same solvent system wash-out, uses 5% methyl alcohol/chloroform wash-out then.Mix suitable fraction and concentrated, obtain 0.76g(2.13mmol; 73%) oil.This oil is dissolved in the EC, adds ether-HCl and is settled out hydrochloride, obtains 6-O-demethylation-6-O-[2-(methyl) the propyl group carbonyl] the lycoremine hydrochloride, m.p.209-211 ℃ (decomposition).
Analyze:
C
21H
27NO
5HCl calculated value: 64.03% 7.16%H 3.56%N
Measured value: 63.79%C 7.04%H 3.45%N
Embodiment 36
6-O-demethylation-6-O-(n-nonyl carbonyl) lycoremine hydrochloride
With 1.62g(13.23mmol) 4-dimethylaminopyridine (being dissolved in the 1.0ml methylene dichloride) is added to the 1.99g(7.29mmol of stirring) 6-O-piptonychia lycoremine is in the mixture of 5.0ml methylene dichloride.Cooling mixture to 0 ℃ adds 3.13g(9.50mmol afterwards) capric anhydride (being dissolved in the 0.5ml methylene dichloride).Stirring at room gained mixture 1.5 hours cooled off 1.5 hours in ice bath afterwards, and temperature rises to room temperature, was filled on the flash chromatography post of filling with silica gel and 3% methyl alcohol/chloroform, with same solvent system wash-out, used 5% methyl alcohol/chloroform wash-out then.Mix suitable fraction and concentrate, obtain the product and the oily mixture of high-grade wash-out impurity slightly.Should oil chromatography on silica gel, with 3% methyl alcohol/chloroform wash-out.Mixing contains the fraction of expecting product and concentrates, and obtains impure a little oil, with Waters Prep 500 HPLC instrument purifying, with 2% methyl alcohol/chloroform wash-out.Mix the pure fraction that contains product and also concentrate, obtain 1.78g(4.16mmol, 57%) oil.Use ether-HCl deposited salt hydrochlorate, obtain 6-O-demethylation-6-O-(n-nonyl carbonyl) the lycoremine hydrochloride, m.p.162-164 ℃.
Analyze:
C
26H
37NO
4HCl calculated value: 67.30%C 8.25%H 3.02%N
Measured value: 67.28%C 8.18%H 2.84%N
Embodiment 37
6-O-demethylation-6-O-(n-octyloxy carbonyl) lycoremine hydrochloride
With 0.49ml(0.55g, 3.65mmol) 1,8-diazabicyclo [5.4.0]+one alkane-7-alkene (DBU) is added to the 1.0g(3.66mmol that is in ice bath of stirring) 6-O-demethylation lycoremine is in the suspension of 10ml chloroform.In this solution, add 0.72ml carbonochloridic acid n-octyl with syringe.Stirred this solution in the ice bath 4.5 hours, and in the impouring refrigerative saturated sodium bicarbonate, used extracted with diethyl ether, handle water layer with sodium-chlor, and with twice of extracted with diethyl ether.Mix ether extraction liquid N
A2SO
4Oil is filtered and be condensed into to drying, and this oil flash chromatography and purifying is used chloroform on silica gel is 3% methyl alcohol/chloroform wash-out then.Mix and contain the pure fraction of product and be condensed into oil (0.44g, 0.102mmol, 27.9%), this oil is dissolved in ether, add ether-HCl and be settled out hydrochloride.Obtain 0.27g6-O-demethylation-6-O-(n-octyloxy carbonyl at 80 ℃ of vacuum-drying white solids) the lycoremine hydrochloride, m.p.171-174 ℃.
Analyze:
C
25H
35NO
5HCl calculated value: 64.43%C 7.79%H 3.01%N
Measured value: 64.12%C 7.86%H 3.03%N
Embodiment 38
6-O-demethylation-3-O-(tert-butoxycarbonyl)-and 6-O-(tertiary butyl carbonyl) the lycoremine hydrochloride
With 4-Dimethylamino pyridine (0.85g, 0.007mol) be added to 6-O-demethylation-6-O-(tertiary butyl carbonyl) lycoremine (2.2g, 0.0062mol) in the cold soln of 75ml methylene dichloride, (1.5ml is 0.0062mol) in the solution of 10ml methylene dichloride to add the dimethyl dicarbonate butyl ester then.
After the stirring at room 40 hours, mixture is added on the silicagel column, through HPLC with 3% ethanol/methylene wash-out.Evaporation expectation fraction gets yellow viscous oil, 1.7g(60%); It is dissolved in methyl alcohol, and being acidified to PH with ether-HCl is 1, dilutes with ether then.Collect the white precipitate and the drying that produce, obtain the 1.1g product, m.p.194 ℃ (decomposition).
Analyze:
C
26H
35NO
6HCl calculated value: 63.21%C 7.35%H 2.84%N
Measured value: 63.47%H 7.42%H 2.83%N
Embodiment 39
6-O-demethylation-6-O-(4-trifluoromethyl carbonyl) lycoremine
With triethylamine (0.9ml, 0.0062mol) and 4-Dimethylamino pyridine (0.1g, 0.001mol) be added to 6-O-demethylation lycoremine (1.7g, 0.0062mol) in the cold soln of 60ml methylene dichloride, (0.9ml is 0.0062mol) in the solution of 10ml methylene dichloride to add the 4-trifluoromethyl benzoyl chloride then.
After the stirring at room 20 hours, mixture is added on the silicagel column, with 3% ethanol/methylene through the HPLC wash-out.Mix expectation fraction and evaporation, obtain white solid product, 2.6g(90%), m.p.148-150 ℃.
Analyze:
C
24H
22F
3NO
4Calculated value: 64.71%C 4.98%H 3.15%N
Measured value: 64.45%C 4.99%H 3.02%N
Embodiment 40
6-O-demethylation-6-O-(2-methylbutane-2-base carbonyl) lycoremine hydrochloride
With 1.01g(3.70mmol) 6-O-demethylation lycoremine is added to the 0.46ml(3.68mmol of stirring) 2, the 2-acid dimethyl is in the solution of 3.7ml anhydrous chloroform, add 0.76g(3.67mmol then) 1,3-dicyclohexylcarbodiimide and 0.45g(3.68mmol) Dimethylamino pyridine.Stirring at room reaction mixture 23 hours is filled on the flash chromatography post of filling with the silica gel that is dipped in 3% methyl alcohol/chloroform then, with same solvent system wash-out, uses 5% methyl alcohol/chloroform wash-out then.Mix expectation fraction and concentrated, obtain 1.07g and be bordering on the xanchromatic solid.This solid is dissolved in the ether, adds ether-HCl and be settled out hydrochloride, obtain the material that m.p. is 235-238 ℃ (decomposition) after the drying.
Analyze:
C
22H
29NO
4HCl calculated value: 64.78%C 7.41%H 3.43%N
Measured value: 64.63%C 7.70%H 3.54%N
Embodiment 41
6-O-demethylation-6-O-(2-hydroxyethyl) lycoremine half hydrochloride hydrate
With 1.1g(3.07mmol) 6-O-demethylation-6-O-(ethoxycarbonylmethyl group) lycoremine is added to 4.6ml(4.6mmol with syringe in the solution of 10.0ml tetrahydrofuran (THF) under 0 ℃) in lithium aluminum hydride (1M is in the tetrahydrofuran (THF)) solution.This solution of stirring at room 1 hour, be cooled to again 0 ℃ 10 minutes, with 1.0ml distilled water quenching twice, use the quenching of 1.0ml15% sodium hydroxide then.With the reaction mixture of chloroform extraction quenching 3 times.Mix organic layer, use N
A2SO
4White solid is filtered and be condensed into to drying.This solid is dissolved in the chloroform, is filled on the flash chromatography post of filling, with same solvent system wash-out with the silica gel that is dipped in 5% methyl alcohol/chloroform.Mix suitable fraction and be condensed into white solid (0.67g).This solid is dissolved in ether, adds ether-HCl and be settled out hydrochloride, obtain the 0.44g product, m.p.210-212 ℃ (decomposition).
Analyze:
C
18H
23NO
4HCl calculated value: 59.58%C 6.94%H 3.86%N
Measured value: 59.13%C 6.81%H 3.81%N
It should be understood that this specification sheets obtains explanation by embodiment, and, under the prerequisite that does not deviate from the defined the spirit and scope of the present invention of appended claims, can make various modifications and variations without any restriction.
Claims (10)
1, a kind of compound of formula II
Wherein:
R
1Be hydrogen, (C
1～C
12) alkyl-carbonyl, (C
1～C
12) alkoxy carbonyl, aryl (C
1～C
12) alkyl amino-carbonyl, single (C
1～C
18) alkyl amino-carbonyl or two (C
1～C
8) alkyl amino-carbonyl;
R
2Be (C
1～C
12) alkyl carbonyl oxy, aryl (C
1～C
4) alkyl carbonyl oxy, (C
1～C
12) alkoxyl group carbonyl oxygen base, aryl-carbonyl oxygen, hydroxyl, (C
1～C
6) carbalkoxy (C
1～C
6) alkoxyl group or hydroxyl or hydroxyl (C
1～C
10) alkoxyl group;
R
3Be hydrogen, halogen or (C
1～C
4) alkyl; With its a kind of pharmaceutically acceptable addition salt;
Condition is R
2During for hydroxyl, R
1And R
3Can not all be hydrogen.
2, press the compound of the defined a kind of formula II of claim 1, wherein R
3Be hydrogen or halogen.
3, press the compound of the defined a kind of formula II of claim 2, wherein R
1Be hydrogen, (C
1～C
12) alkyl-carbonyl or (C
1～C
12) alkoxy carbonyl; R
2Be (C
1～C
12) alkyl carbonyl oxy, phenyl carbonyl oxygen base, (C
1～C
12) alkoxyl group carbonyl oxygen base, hydroxyl, (C
1～C
6) alkoxy carbonyl (C
1～C
6) alkoxyl group; Or hydroxyl (C
1-C
6) alkoxyl group;
Condition is R
2During for hydroxyl, R
1And R
3Not all be hydrogen.
4, press the compound of the defined a kind of formula II of claim 1, wherein
R
1Be hydrogen, (C
1～C
8) alkyl-carbonyl or (C
1～C
6) carbalkoxy;
R
2Be (C
1～C
10) alkyl carbonyl oxy or phenyl carbonyl oxygen base; And
R
3Be hydrogen or bromine.
5, press the compound of the defined a kind of formula II of claim 1, wherein
R
1Be hydrogen, methyl carbonyl, ethyl carbonyl, sec.-propyl carbonyl, tertiary butyl carbonyl or n-heptyl carbonyl;
R
2Be methyl carbonyl oxygen base, ethyl oxy carbonyl, sec.-propyl carbonyl oxygen base, tertiary butyl carbonyl oxygen base, n-heptyl carbonyl oxygen base, phenyl carbonyl oxygen base, trifluoromethyl carbonyl oxygen base, aminomethyl phenyl carbonyl oxygen base, xylyl carbonyl oxygen base or hydroxyl; And
R
3Be hydrogen or bromine.
6, by the compound of the defined formula II of claim 1, this compound is 6-O-demethylation-6-O-(pivaloyl) lycoremine or its pharmaceutically-acceptable acid addition.
7, by the compound of the defined formula II of claim 1, this compound is 6-O-demethylation-6-O-(2-propoxycarbonyl) lycoremine or its pharmaceutically-acceptable acid addition.
8, by the compound of the defined formula II of claim 1, this compound is 6-O-demethylation-3-O-(2-propoxycarbonyl)-6-O-(tertiary butyl carbonyl) lycoremine or its pharmaceutically-acceptable acid addition.
9, a kind of pharmaceutical composition, it comprises by the compound of the defined a kind of formula II of claim 1 and a kind of pharmaceutically acceptable carrier.
10, by the purposes of compound in medication preparation of the defined formula II of claim 1, this medicine is used for the treatment of the memory machine dysfunction that is reduced to feature with choline function.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US137444 | 1993-10-15 | ||
| US08/137,444 US6316439B1 (en) | 1993-10-15 | 1993-10-15 | Galanthamine derivatives as acetylcholinesterase inhibitors |
| US137,444 | 1993-10-15 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1108657A true CN1108657A (en) | 1995-09-20 |
| CN1039910C CN1039910C (en) | 1998-09-23 |
Family
ID=22477461
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN94117062A Expired - Lifetime CN1039910C (en) | 1993-10-15 | 1994-10-14 | Calanthamine derivatives, a process for their preparation and their use as medicaments |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US6316439B1 (en) |
| EP (1) | EP0649846B1 (en) |
| JP (1) | JP2664343B2 (en) |
| KR (1) | KR100227957B1 (en) |
| CN (1) | CN1039910C (en) |
| AT (1) | ATE211474T1 (en) |
| AU (1) | AU696170B2 (en) |
| CA (1) | CA2118172C (en) |
| CZ (1) | CZ283731B6 (en) |
| DE (1) | DE69429570T2 (en) |
| DK (1) | DK0649846T3 (en) |
| EG (1) | EG20726A (en) |
| ES (1) | ES2170759T3 (en) |
| FI (1) | FI108722B (en) |
| IL (1) | IL111275A (en) |
| NO (1) | NO307464B1 (en) |
| NZ (1) | NZ264682A (en) |
| PL (1) | PL177549B1 (en) |
| PT (1) | PT649846E (en) |
| RO (1) | RO114134B1 (en) |
| RU (1) | RU2109743C1 (en) |
| TW (1) | TW289754B (en) |
| ZA (1) | ZA948061B (en) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT403803B (en) | 1996-04-19 | 1998-05-25 | Sanochemia Ltd | NEW BENZAZEPINE DERIVATIVES, THESE MEDICINAL PRODUCTS AND THE USE THEREOF FOR THE PRODUCTION OF MEDICINAL PRODUCTS |
| MXPA02005667A (en) * | 1999-12-10 | 2004-09-10 | Bonnie Davis | Analogs of galanthamine and lycoramine as modulators of nicotinic receptors. |
| CN101100472A (en) * | 2001-04-30 | 2008-01-09 | 美国拜尔公司 | 4-amino-5,6-substituted thiopheno [2,3-D] pyrimidines compound and its uses |
| US20030162770A1 (en) * | 2002-02-22 | 2003-08-28 | Davis Bonnie M. | Use of modulators of nicotinic receptors for treatment of cognitive dysfunction |
| US20040254146A1 (en) * | 2002-05-21 | 2004-12-16 | Nastech Pharmaceutical Company Inc. | Carboxylate salts of galantamine and their pharmaceutical use |
| US20050143350A1 (en) * | 2003-11-19 | 2005-06-30 | Seed John C. | Combination drug therapy to treat obesity |
| CA2551946A1 (en) * | 2003-12-31 | 2005-07-21 | Actavis Group Hf | Immediate, controlled and sustained release formulations of galantamine |
| WO2005065662A1 (en) * | 2003-12-31 | 2005-07-21 | Actavis Group Hf | Solid dosage formulations of galantamine |
| JPWO2006004201A1 (en) * | 2004-07-01 | 2008-04-24 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Nerve regeneration promoter |
| EP2425846A1 (en) * | 2004-12-23 | 2012-03-07 | Voyager Pharmaceutical Corporation | Acetylcholinesterase Inhibitors and leuprolide acetate for the treatment of Alzheimer's disease |
| EP1895995A2 (en) * | 2005-05-13 | 2008-03-12 | Alza Corporation | Multilayer drug system for the delivery of galantamine |
| US20080188510A1 (en) * | 2005-05-23 | 2008-08-07 | Eisai R & D Management Co., Ltd. | Novel methods using zonisamide |
| US20090253654A1 (en) | 2005-09-22 | 2009-10-08 | Galantos Pharma Gmbh | Cholinergic enhancers with improved blood-brain barrier permeability for the treatment of diseases accompanied by cognitive impairment |
| WO2007035941A2 (en) * | 2005-09-23 | 2007-03-29 | Alza Corporation | Transdermal galantamine delivery system |
| JP5504253B2 (en) | 2008-04-14 | 2014-05-28 | ニューロダイン ライフ サイエンス インコーポレイテッド | Galantamine derivatives as prodrugs for the treatment of human brain disease |
| CA2768668A1 (en) * | 2009-07-23 | 2011-01-27 | Shire Llc | Galantamine amino acid and peptide prodrugs and uses thereof |
| AU2015258814B2 (en) * | 2014-05-16 | 2018-04-05 | Synaptec Development Llc | Clearance of amyloid ss |
| EP4029867A1 (en) | 2021-01-13 | 2022-07-20 | Alpha Cognition Inc. | Solid forms of galantamine benzoate gluconate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL122665B1 (en) | 1978-11-21 | 1982-08-31 | Edinen Zentar Chim | Process for preparing novel dienones of narvedine type and their derivatives |
| US4663318A (en) | 1986-01-15 | 1987-05-05 | Bonnie Davis | Method of treating Alzheimer's disease |
| US6150354A (en) * | 1987-01-15 | 2000-11-21 | Bonnie Davis | Compounds for the treatment of Alzheimer's disease |
| KR100195399B1 (en) * | 1987-05-04 | 1999-06-15 | 보니데이비스 | Compounds for the treatment of alzheimer's disease |
| NL8800350A (en) | 1988-02-12 | 1989-09-01 | Stichting Biomedical Research | New 6-O-demethyl-galanthamine derivs. - useful as anti-cholinesterase agents |
| WO1992020327A1 (en) | 1991-05-14 | 1992-11-26 | Ernir Snorrason | Treatment of fatigue syndrome with cholinesterase inhibitors |
| US5153193A (en) | 1991-10-01 | 1992-10-06 | Hoechst-Roussel Pharmaceuticals Incorporated | Carbamate derivatives of 4-amino-3-isoxazolidinones, 3-amino-1-hydroxypyrrolidin-2-ones and 1-amino-1-cyclopropanecarboxylic acid analogs |
-
1993
- 1993-10-15 US US08/137,444 patent/US6316439B1/en not_active Expired - Lifetime
-
1994
- 1994-10-10 EP EP94115961A patent/EP0649846B1/en not_active Expired - Lifetime
- 1994-10-10 AT AT94115961T patent/ATE211474T1/en active
- 1994-10-10 PT PT94115961T patent/PT649846E/en unknown
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